Giving an Enzyme Scissors: Serotonin Derivatives as Potent Organocatalytic Switches for DNA Repair Enzyme OGG1

The base excision
repair enzyme 8-oxoguanine DNA glycosylase 1
(OGG1) plays a central role in maintaining genome integrity and mediating
cellular responses to oxidative stress. As such, it represents an
attractive target for pharmaceutical modulation. Small-molecule organocatalytic
switches (ORCAs) greatly enhance the rate of OGG1-catalyzed cleavage
of DNA abasic sites, thereby accelerating DNA repair. Here, we present
the discovery and hit-to-lead optimization of a novel class of highly
potent serotonin-derived ORCAs with greatly improved pharmacokinetic
properties. Biochemical assays, X-ray crystallography, and molecular
dynamics simulations point toward a water-mediated mechanism of activation,
distinct from previously proposed Brønsted base-assisted models.
These findings establish serotonin-based ORCAs as promising chemical
probes and potential leads for therapeutic modulation of OGG1 in oxidative
stress-driven diseases.